Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds.
• the compounds inhibit GSK-3 and may be useful for the treatment of various disorders of the central nervous system.
• GSK-3 is a proline directed serine/threonine kinase that carries out the phosphorylation of multiple protein substrates. Many of these proteins are involved in the regulation of numerous diverse cellular functions, including metabolism, differentiation, proliferation and apoptosis.
• GSK-3 is constitutively active, with its base level of activity being positively modulated by phosphorylation on Tyr216/219, depending on isoform.
• GSK-3 has a unique substrate selectivity profile that is distinguished by the strong preference for the presence of a phosphorylated residue optimally located four amino acids C-terminal to the site of GSK-3 phosphorylation. Most commonly, GSK-3 activity is associated with inducing a loss of substrate function, such that GSK-3 inhibition will frequently result in increased downstream substrate activity.
• GSK-3 exists in two isoforms, GSK-3a (51 kDa) and GSK-3 (47kDa),that share 84% overall identity and greater than 98% identity within their respective catalytic domains. Both primary isoforms are ubiquitously expressed, with high levels observed in the brain, particularly in the cortex and hippocampus. In most brain areas, GSK-3 ⁇ is the predominant isoform. However, some studies suggest that GKS-3oc and ⁇ 8 ⁇ -3 ⁇ share very similar, if not entirely redundant functions in a number of cellular processes. The activity of GSK-3 ⁇ is significantly reduced by phosphorylation at Ser9 in the N-terminal domain, most notably by protein kinase B (PKB or AKT). This inhibitory pathway has been proposed to result in
• AD pathology is prominently associated with the formation of beta-amyloid ( ⁇ ) plaques, soluble forms of ⁇ such as ⁇ 1-42 that are associated with increased neuronal toxicity, and neurofibrillary tangles (NFTs).
• ⁇ beta-amyloid
• NFTs neurofibrillary tangles
• the uncomplexed hyperphosphorylated tau assembles into paired helical filaments (PHFs) that aggregate to produce the stereotypic intracellular NFTs associated with AD.
• PHFs paired helical filaments
• Other potential pathological consequences of over-activation of GSK-3 include neuroinflammation and neuronal apoptosis.
• GSK-3 has been demonstrated to be involved in mechanisms underlying memory and learning, and dysregulation of GSK-3 function may explain some of the early cognitive deficits observed in AD.
• GSK-3 is also known to play a key role in glucose metabolism, and was first identified as the enzyme responsible for effecting the inhibitory phosphorylation of glycogen synthase, the result of which is to reduce the rate of conversion of glucose to glycogen, giving rise to elevated blood glucose levels. This function of GSK-3 is controlled by insulin. Binding of insulin to its receptor leads indirectly to the activation of AKT and subsequent inhibitory Ser9 phosphorylation of GSK-3.
• GSK-3 activity may be useful in the treatment of both the neuropatho logic and symptomatic aspects of Alzheimer's disease, as well as other neurodegenerative diseases.
• these include, but are not limited to, tauopathies (for example, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease), Parkinson's disease, amyotrophic lateral schlerosis, stroke, Huntington's disease, peripheral neuropathies, traumatic brain injury, spinal cord trauma, and vascular dementias.
• Compounds that inhibit GSK-3 may also have utility in the treatment of diabetes, inflammatory diseases such as rheumatoid arthritis and osteoarthritis, treatment-resistant depression, schizophrenia, bipolar disorder, manic depression, osteoporosis, cardioprotection, and various cancers such as gliomas, non-small cell lung cancer, pancreatic cancer, breast cancer, T- or B-cell leukemia, and multiple myeloma.
• inflammatory diseases such as rheumatoid arthritis and osteoarthritis
• treatment-resistant depression schizophrenia, bipolar disorder, manic depression, osteoporosis, cardioprotection
• various cancers such as gliomas, non-small cell lung cancer, pancreatic cancer, breast cancer, T- or B-cell leukemia, and multiple myeloma.
• the compounds are novel inhibitors of GSK-3 and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability. DESCRIPTION OF THE INVENTION
• the invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions, and their treating disorders associated with GSK-3.
• One aspect of the invention is a compound of formula I
• R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;
• R 2 is hydrogen, cyano, halo, alkyl, cyanoalkyl, haloalkyl, cycloalkyl,
• R 4 is hydrogen or alkyl
• R 5 is hydrogen or alkyl; or N(R 4 )( R 5 ) taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and is substituted with 0-4 halo or alkyl substituents;
• Ar 1 is 3-pyridinyl, 2-pyrazinyl, 4-pyridazinyl, 4-pyrimidinyl, 4-pyrazolyl, 4- isothiazolyl, or 3-imidazopyridazinyl, and is substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl,
• cycloalkyl hydroxyalkyl, (dicycloalkyl)hydroxyalkyl, (hydroxy)haloalkyl, alkoxyalkyl, (N(R 4 )(R 5 ))alkyl, cycloalkyl, hydroxycycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, ((alkyl)cycloalkyl)alkoxy, alkylcarbonyl, cycloalkylcarbonyl, tetrahydrofuranyl, (alkyl)tetrahydrofuranyl, dioxolanyl,
• alkyl)dioxolanyl (cycloalkyl)dioxolanyl, (phenyl)dioxolanyl, (dialkyl)dioxolanyl, (haloalkyl)(alkyl)dioxolanyl, (trialkyl)dioxolanyl, dihydrpyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, N(R 4 )(R 5 ), and Ar 2 ; and is also substituted with 0-1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
• Ar 2 is phenyl, pyridinyl, or pyrazolyl, and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; or a pharmaceutically acceptable salt thereof.
• Another aspect of the invention is a compound of formula I where R 1 is hydrogen or halo.
• Another aspect of the invention is a compound of formula I where R 2 is haloalkyl.
• Another aspect of the invention is a compound of formula I where Ar 1 is 3-pyridinyl substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, (dicycloalkyl)hydroxyalkyl,
• Another aspect of the invention is a compound of formula I where is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.
• variable substituent including R 1, R 2, R 3, R 4, R 5, Ar 1, and Ar 2
• the scope of any instance of a variable substituent can be used independently with the scope of any other instance of a variable substituent.
• the invention includes combinations of the different aspects.
• Halo includes fluoro, chloro, bromo, and iodo.
• Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
• Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
• Alkynyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond.
• Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
• Haloalkyl and “haloalkoxy” include all halogenated isomers from monohalo to perhalo.
• Terms with a hydrocarbon moiety include straight and branched isomers for the hydrocarbon portion.
• “Aryl” means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group.
• Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring.
• Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
• Heteroaryl means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as
• ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
• the invention includes all pharmaceutically acceptable salt forms of the compounds.
• Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
• Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
• Some Formula I compounds contain at least one asymmetric carbon atom, an example of which is shown below.
• the invention includes all stereoisomeric forms of the compounds, both mixtures and separated isomers. Mixtures of stereoisomers can be separated into individual isomers by methods known in the art.
• the invention is intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• Isotopes of carbon include 13 C and 14 C.
• Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties. Synthetic Methods
• Compounds of Formula I may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials.
• the variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention. The schemes encompass reasonable variations known in the art.
• Compounds of Formula I can be synthesized through the following general scheme. Starting from either 2-chloro-isonicotinic acid or iosnicotinic acid dichloride, reaction with commercially available or prepared 3 -amino heterocycles can afford 2-chloro-isonicotinamides of formula II. Reaction of Formula II compounds with substituted 2-amino pyridines can obtain Formula I compounds. Direct amination of 2-chloro-isonicotinic acid with substituted 2-amino pyridines can afford intermediate acids of Formula III, which after amide formation reaction with various 3 -amino heterocycles can also lead to Formula I compounds.
• the kinase assay was performed in V-bottom 384-well plates.
• the final assay volume was 30 ⁇ prepared from 15 ⁇ additions of enzyme, substrates
• the final concentration of reagents in the assay were 250 pM GSK3 or GSK3P, 20 uM ATP, 1.5 uM FL-KRREILSRRP[ps]ERYR-NH2, and 1.6% DMSO.
• Dose response curves were generated to determine the concentration required to inhibit 50%> of the kinase activity (IC 50 ).
• Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at eleven concentrations. IC 50 values were derived by non-linear regression analysis.
• compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• Another aspect of the invention is a method for the treatment for modulation of GSK-3 activity may be useful in the treatment of both the neuropatho logic and symptomatic aspects of Alzheimer's disease, as well as other neurodegenerative diseases. These include, but are not limited to, tauopathies (for example,
• frontotemporal dementia progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease), Parkinson's disease, amyotrophic lateral sclerosis, stroke, Huntington's disease, peripheral neuropathies, traumatic brain injury, spinal cord trauma, and vascular dementias, which comprises administering to a patient a therapeutically affective amount of a compound of formula I.
• Another aspect of the invention is a method for the treatment for diabetes, inflammatory diseases such as rheumatoid arthritis and osteoarthritis, treatment- resistant depression, schizophrenia, bipolar disorder, manic depression, osteoporosis, cardioprotection, and various cancers such as gliomas, non-small cell lung cancer, pancreatic cancer, breast cancer, T- or B-cell leukemia, and multiple myeloma, which comprises administering to a patient a therapeutically affective amount of a compound of formula I.
• inflammatory diseases such as rheumatoid arthritis and osteoarthritis
• treatment- resistant depression schizophrenia, bipolar disorder, manic depression, osteoporosis, cardioprotection
• various cancers such as gliomas, non-small cell lung cancer, pancreatic cancer, breast cancer, T- or B-cell leukemia, and multiple myeloma
• Another aspect of the invention is a method for the treatment of Alzheimer's disease which comprises administering to a patient a therapeutically affective amount of a compound of formula I.
• Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment of Alzheimer's disease.
• Patient means a person suitable for therapy as understood by practitioners in the field of affective disorders and neurodegenerative disorders.
• Treatment Treatment
• therapy Treatment
• related terms are used as understood by practitioners in the field of neurological and psychiatric disorders.
• compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
• Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
• Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example,
• compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
• Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
• agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
• the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
• the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.
• 2-Chloro-N-(4-phenylpyridin-3-yl)isonicotinamide In a 100 mL round-bottom flask was added 2-chloroisonicotinoyl chloride (556 mg, 3.16 mmol) and 4- phenylpyridin-3 -amine dihydrochloride (384 mg, 1.58 mmol) in methylene chloride (14 mL) to give a tan suspension. DIEA (0.910 mL, 5.21 mmol) was added dropwise. The solids dissolved and the resulting greenish solution was stirred at rt for two days.
• N-(4-Phenylpyridin-3-yl)-2-(pyridin-2-ylamino)isonicotinamide In a 5 mL vial was added 2-chloro-N-(4-phenylpyridin-3-yl)isonicotinamide (31.7 mg, 0.102 mmol), pyridin-2-amine (11.6 mg, 0.123 mmol), and Cs 2 C0 3 (50.0 mg, 0.154 mmol) in dioxane (0.6 mL) to give a tan suspension under nitrogen.
• PdOAc 2 0.19 mg, 4.09 ⁇
• XANTPHOS 3.55 mg, 6.14 ⁇
• the vial was sealed under nitrogen, and the mixture was heated at 100°C overnight. After 18 h, LCMS showed ca 60% conversion to the desired product. The mixture was diluted with water and ethyl acetate. The layers were separated. The organic layer was dried and concentrated.
• the vial was degassed and flushed with N 2 three times and the vessel was capped and placed in a preheated oil bath at 110 °C for 10 h.
• the sample was cooled to rt, diluted with ethyl acetate, and washed with water.
• the aqueous layer was acidified to pH 5-6 and extracted with ethyl acetate.
• the organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to give the desired product (1.35 g, 4.77 mmol, 38% yield).
• the solid was collected by filtration and dried under vacuo to give more of the desired product (1.9 g, 6.71 mmol, 53% yield).
• the aqueous was separated and washed with ethyl acetate two more times. The ethyl acetate layer was discarded. The aqueous was adjust to PH ⁇ 4 by adding IN HC1. The aqueous was extract three more times with ethyl acetate. The ethyl acetate layer was combined, dried (Na2S04), filtered and concentrated to give the crude as a yellow solid (116.5 mg, 74% yield). MS (ES+) m/e 250 [M+H] + .
• Methyl 2-((5-(2-cyanopropan-2-yl)pyridin-2-yl)amino)isonicotinate To an oven dried vial with a stir bar, brettphos (5.83 mg, 0.011 mmol), brettphos precatalyst (8.84 mg, 0.011 mmol), 2-(6-chloropyridin-3-yl)-2-methylpropanenitrile (0.2 g, 1.107 mmol), methyl 2-aminoisonicotinate (0.168 g, 1.107 mmol)and K2C03 (0.230 g, 1.661 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x).
• l-(6-Aminopyridin-3-yl)cyclopropanecarbonitrile A mixture of l-(6- chloropyridin-3-yl)cyclopropanecarbonitrile (0.5 g, 2.80 mmol), BINAP (0.174 g, 0.280 mmol)and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (2.56 g, 2.80 mmol)in Toluene (15 mL) was degassed with N2 for 10 min. To this mixture was added diphenylmethanimine (0.515 mL, 3.08 mmol) and SODIUM TERT- BUTOXIDE (0.350 g, 3.64 mmol)).
• the mixture was heated at 90 °C for 4.0 h. LCMS showed desired M+H.
• the mixture was then diluted with EtO Ac/water/brine (brine for better separation), filtered through a pad of wet celite to remove insoluble material.
• the organic layer was collected and washed with brine, dried over sodium sulfate and concentrated to give the crude imine.
• the crude imine was dissolved in THF (12 mL) and was treated with 6.0 N HC1 for 30 min. The reaction was left stirring at rt overnight.
• the mixture was then diluted with EtOAc, the aqueous was collected (through a filter to remove insoluble material) and the organic was further extratcted with 4.0 N HC1 (2X10 mL).
• the solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (2mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 110 °C for 10 hrs. The sample was cooled to rm temp, diluted with ethyl acetate and washed with water. The aq layer was acidified to pH5-6 and extracted with ethyl acetate. The org extracts were combined and dried over sodium sulfate.
• N-(4-Phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide To 3-amino-4-phenyl-pyridine (2.65 g, 15.6 mmol) and 2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid (4.2 g, 15 mmol) in ethyl acetate (50 mL) was added DIEA (12.9 mL, 74.2 mmol) followed by 1- propanephosphonic acid cyclic anhydride, 50% (by weight) in ethyl acetate (18.9 g, 29.7 mmol) dropwise.
• N-(4-(l-Hydroxyethyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide was added to the MeOH (3 mL) solution of N-(4-acetylpyridin-3-yl)-2-((5- (trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (5 mg, 0.012 mmol) at rt. The reaction was stirred for 20 min. The solvent was removed via vacuum and the product was purified via SCP.
• N-(6-Chloro-4-(l-cyclopropyl-l-hydroxyethyl)pyridin-3-yl)-2-((5- (trifluoromethyl)pyridin-2-yl)amino)isonicotinamide Methylmagnesium bromide (0.1 mL, 0.300 mmol) was added to the THF (1 mL) solution of N-(6-chloro-4- (cyclopropanecarbonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide (1.8 mg, 3.90 ⁇ ) at room temperature.
• nitropyridine ether a light-yellow oil.
• a solution of crude 4-(2,2-difiuoroethoxy)-3- nitropyridine (1.84 g, 9.01 mmol) in ethanol (40 mL) was degassed for 10 minutes with nitrogen and then 10% palladium on carbon (0.16 g) was carefully added. The mixture was stirred under 1 atm. of hydrogen overnight. The mixture was then degassed with nitrogen, and carefully filtered through celite. The filtrated was concentrated in vacuo, and the light-brown oil flushed with methylene chloride. The crude amine was used without further purification.
• 6-Fluoro-4-(2,2,2-trifluoroethoxy)pyridin-3-amine A mixture of Pd/C (14.6 mg, 0.014 mmol) and 2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)pyridine (228 mg, 0.951 mmol) in ethanol (4 mL) was stirred under hydrogen (1 atm) at room tenperature overnight. The mixture was degassed before filtration through celite. The filtrate was concentrated and the product was purified by via flash chromatography on silica gel, eluting with methanol in methylene chloride from 0 to 10% to give the product as a tan solid (134 mg, 66%).
• 2,4-Difluoro-5-nitropyridine In a 250 mL round-bottom flask was added 2,4- dichloro-5-nitropyridine (0.73 g, 3.8 mmol), potassium fluoride (0.659 g, 11.3 mmol), and 18-crown-6 (0.160 g, 0.605 mmol) in N-methylpyrrolidinone (3 mL) to give a tan suspension. The mixture was heated at 100°C under nitrogen for 3 h. The mixture was then partitioned between water and ether/hexane.
• 6-Fluoro-4-morpholinopyridin-3-amine 6-Fluoro-4-morpholinopyridin-3-amine.
• 4-(2-fluoro-5-nitropyridin-4-yl)morpholine (209 mg, 0.920 mmol)
• methanol 6 mL
• Pd/C 98.0 mg, 0.092 mmol
• 6-Chloro-4-phenylpyridin-3-amine 6-chloro-4-phenylpyridin-3-amine.
• 6-chloro-4- iodopyridin-3 -amine 186 mg, 0.731 mmol
• phenylboronic acid 143 mg, 1.170 mmol
• Na 2 CC"3 1.096 mL, 2.193 mmol
• dioxane 4 mL
• 1 '-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene (30.1 mg, 0.037 mmol) was added under nitrogen.
• 6-Methyl-4-phenylpyridin-3-amine 6-chloro-4- phenylpyridin-3 -amine (44.2 mg, 0.216 mmol), methylboronic acid (64.6 mg, 1.080 mmol), and potassium carbonate (59.7 mg, 0.432 mmol) in dioxane (1 mL)
• tert-Butyl [2,4'-bipyridin]-3'-ylcarbamate To a pressure vessel was added tert- butyl (4-iodopyridin-3-yl)carbamate (0.25g, 0.781 mmol), 2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (0.176 g, 0.859 mmol) and PdC12(dppf)-
• tert-Butyl (5-fluoropyridin-3-yl)carbamate In a 250 mL round-bottom flask was added 3-bromo-5-fluoropyridine (2.84 g, 16.1 mmol), tert-butyl carbamate (2.080 g, 17.75 mmol), and CS 2 CO 3 (10.52 g, 32.3 mmol) in dioxane (40 mL) (degassed) to give a colorless suspension under nitrogen. Pd 2 (dba) 3 (0.443 g, 0.484 mmol) and XANTPHOS (0.374 g, 0.646 mmol) were added. The flasked was heated at 100°C under nitrogen overnight for 20 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by flash column
• tert-Butyl (5-fluoro-4-iodopyridin-3-yl)carbamate In a 500 mL round-bottom flask was dissolved tert-butyl (5-fluoropyridin-3-yl)carbamate (1.802 g, 8.49 mmol) and ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylethylenediamine (3.84 mL, 25.5 mmol) in ethyl ether (40 mL) to give a light yellow solution. After cooling to -78°C, n-BuLi (9.69 mL, 25.5 mmol) was slowly added via syringe (to maintain the temperature below -60°C).
• tert-Butyl (5-fluoro-4-phenylpyridin-3-yl)carbamate In a 15 mL vial was dissolved tert-butyl (5-fluoro-4-iodopyridin-3-yl)carbamate (188.3 mg, 0.557 mmol), phenylboronic acid (109 mg, 0.891 mmol), and Na 2 C0 3 (0.835 mL, 1.67 mmol) in dioxane (3 mL) to give a slightly yellow solution under nitrogen.
• tert-Butyl (6-chloro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3- yl)carbamate.
• BuLi (2.166 mL, 5.70 mmol) was added to the diethyl ether (17 mL) solution of TMEDA (0.706 mL, 4.68 mmol) and tert-butyl (6-chloropyridin-3- yl)carbamate (0.4653 g, 2.035 mmol) at -78 °C. The reaction was stirred at this temperature for 1 hour.
• tert-Butyl (6-chloro-4-(l-hydroxycyclohexyl)pyridin-3-yl)carbamate was added to the diethyl ether (10 mL) solution of TMEDA (0.467 mL, 3.09 mmol) and tert-butyl (6-chloropyridin-3-yl)carbamate (0.3075 g, 1.345 mmol) at -78 °C. The reaction was stirred at this temperature for 1 hour.
• tert-Butyl (6-chloro-4-(l-hydroxypropyl)pyridin-3-yl)carbamate was added to the diethyl ether (10 mL) solution of TMEDA (0.638 mL, 4.22 mmol) and tert-butyl (6-chloropyridin-3-yl)carbamate (0.483 g, 2.112 mmol) at -78 °C. The reaction was stirred at this temperature for 0.5 hour.
• tert-Butyl (4-(3-fluorooxetan-3-yl)pyridin-3-yl)carbamate To tert-butyl (4-(3- hydroxyoxetan-3-yl)pyridin-3-yl)carbamate (0.1 lg, 0.413 mmol) in CH2C12 (2.5 mL) at -78 °C was added DAST (0.055 mL, 0.413 mmol). The reaction mixture was stirred for lhr at -78 °C then quenched with water. The reaction mixture was warmed to rt then extracted with DCM. The org extracts were combined and dried over sodium sulfate, filtered and concentrated.
• tert-Butyl (6-chloro-4-isobutyrylpyridin-3-yl)carbamate.
• 1H NMR 400MHz, CHLOROFORM-d
• tert-Butyl (6-chloro-4-(cyclopropanecarbonyl)pyridin-3-yl)carbamate.
• ETHYLENE GLYCOL (0.379 mL, 6.80 mmol) and l-(3-aminopyridin-4- yl)ethanone (0.4631 g, 3.40 mmol) in Toluene (5 mL) was heat to reflux for over night. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2S04), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product (59.8 mg obtained, 8% yield) as a wax.
• 6-Chloro-4-(2,4,5-trimethyl-l,3-dioxolan-2-yl)pyridin-3-amine 6-Chloro-4-(2,4,5-trimethyl-l,3-dioxolan-2-yl)pyridin-3-amine.
• the mixture of p- toluenesulfonic acid monhydrate (0.034 g, 0.179 mmol), butane-2,3-diol (0.5 mL, 0.060 mmol) and l-(5-amino-2-chloropyridin-4-yl)ethanone (0.0102 g, 0.060 mmol) in Toluene (4 mL) was heat to reflux for 3 hours.
• 6-Chloro-4-(2-methyl-l,3-dioxolan-2-yl)pyridin-3-amine 6-Chloro-4-(2-methyl-l,3-dioxolan-2-yl)pyridin-3-amine.
• the mixture of p- toluenesulfonic acid monhydrate (7.59 mg, 0.040 mmol), ethylene glycol (0.111 mL, 1.995 mmol) and tert-butyl (4-acetyl-6-chloropyridin-3-yl)carbamate (0.108 g, 0.399 mmol) in Toluene (5 mL) was heat to reflux for over night.
• the reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2S04), filtered and concentrated.
• 6-Chloro-4-(2-ethyl-l,3-dioxolan-2-yl)pyridin-3-amine 6-Chloro-4-(2-ethyl-l,3-dioxolan-2-yl)pyridin-3-amine.
• the mixture of p- toluenesulfonic acid monhydrate (5.01 mg, 0.026 mmol), ethylene glycol (0.2 mL, 3.59 mmol) and tert-butyl (6-chloro-4-propionylpyridin-3-yl)carbamate (0.025 g, 0.088 mmol) in Toluene (2 mL) was heat to reflux for 2 hours.
• the reaction was diluted with ethyl acetate and washed with water three times.
• 6-Chloro-4-(2-ethyl-4,5-dimethyl-l,3-dioxolan-2-yl)pyridin-3-amine 6-Chloro-4-(2-ethyl-4,5-dimethyl-l,3-dioxolan-2-yl)pyridin-3-amine.
• the mixture of p-toluenesulfonic acid monhydrate (3.95 mg, 0.021 mmol), butane -2,3- diol (0.2 mL, 0.069 mmol) and tert-butyl (6-chloro-4-propionylpyridin-3- yl)carbamate (0.0197 g, 0.069 mmol) in Toluene (1 mL) was heat to reflux for 2 hours.
• 6-Chloro-4-(2-ethyl-4-methyl-l,3-dioxolan-2-yl)pyridin-3-amine 6-Chloro-4-(2-ethyl-4-methyl-l,3-dioxolan-2-yl)pyridin-3-amine.
• the mixture of p-toluenesulfonic acid monhydrate (0.030 g, 0.158 mmol), propane- 1,2-diol (0.05 mL, 0.158 mmol) and tert-butyl (6-chloro-4-propionylpyridin-3-yl)carbamate (0.045 g, 0.158 mmol) in Toluene (0.5 mL) was heated to reflux for 2 hours.
• Methyl 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinate To a solution of methyl 4-chloro-6-methylnicotinate (0.371 g, 2 mmol) in dioxane (3 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.762 g, 3.00 mmol), potassium acetate (0.589 g, 6.00 mmol) and PdC ⁇ dppfJ-CF ⁇ C Axlduct
• Methyl 4-(cyclopropanecarbonyl)-6-methylnicotinate To a suspension of crude boronate ester (554 mg, 2 mmol) with bis(triphenylphosphine)palladium(II) dichloride (23.44 mg, 0.033 mmol), potassium phosphate tribasic (532 mg, 2.505 mmol) and water (0.068 mL, 3.76 mmol) in toluene (8.35 mL) was added cyclopropanecarbonyl chloride (0.156 mL, 1.67mmol). The reaction mixture was heated to 80 °C for ⁇ 18h.
• the ethyl acetate layer was separated and washed with water two more times.
• the ethyl acetate layer was separated, dried(Na 2 S0 4 ), filtered and concentrated to give the crude product as a yellow solid.
• the product was purified via flash column eluted with ethyl acetate in hexane from 0 to 100% and gave the desired product as a white solid (0.1937g, 27% yield).
• the product was purified by flash column eluted with ethyl acetate in hexane from 0 to 25%.
• the product obtained is the mixture of mono, bis bromides as well as the unreacted starting material.
• the crude was used as it is.
• 5-Bromo-2-fluoroisonicotinaldehyde The suspension of 5-bromo-4- (bromomethyl)-2-fluoropyridine compound with 5-bromo-4-(dibromomethyl)-2- fluoropyridine (1 : 1) (5.6 g, 9.08 mmol) and Calcium carbonate (4.54 g, 45.4 mmol) in DMSO (12 mL) was stirred at 145 °C for 3 hours. The reaction was filtered and the solid was washed with ethyl acetate. The filtrate was diluted more with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na 2 S0 4 ), filtered and concentrated.
• XANTPHOS (5.09 mg, 8.80 ⁇ ), cesium carbonate (0.048 g, 0.147 mmol), palladium acetate (1.317 mg, 5.87 ⁇ ), 2-((5-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide (0.041 g, 0.147 mmol) and 5-bromo-2-methoxy-4-(2- methyl-l,3-dioxolan-2-yl)pyridine (0.060 g, 0.147 mmol) in Dioxane (1.5 mL) was heated at 110 °C for 5 hours under N 2 . The reaction was partitioned between ethyl acetate and water.
• the ethyl acetate layer was separated and washed two more times with water.
• the ethyl acetate layer was dried(Na 2 S0 4 ), filtered and concentrated.
• the crude was purified via flash column eluted with ethyl acetate in hexane from 0 to 45% to 80% (obtained 8.0 mg,l 1 % yield).
• N-(5-Bromopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide To 5-bromopyridin-3-amine (0.096 g, 0.556 mmol) and 2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid (0.15 g, 0.530 mmol) in DMF (10 mL) was added DIEA (0.463 mL, 2.65 mmol) followed by 1- Propanephosphonic acid cyclic anhydride (1.546 mL, 2.65 mmol) dropwise. The reaction was stirred at rt overnight.
• N-(5- bromopyridin-3 -yl)-2-((5 -(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.02 g, 0.046 mmol)
• RockPhos (0.428 mg, 0.913 (0.042 g, 0.046 mmol)
• lH-pyrazole-4-carbonitrile (4.25 mg, 0.046 mmol)
• K3P04 (9.69 mg, 0.046 mmol) were added.
• the solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (lmL) was added.
• N-(5-Morpholinopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide To an oven dried microwave vial was added N-(5- bromopyridin-3-yl)-2-((5-(trifiuoromethyl)pyridin-2-yl)amino)isonicotinamide (0.025 g, 0.057 mmol), XPhos (2.176 mg, 4.56 ⁇ ) and Pd2(dba)3 (2.090 mg, 2.282 ⁇ ). The solid mixture was degassed and flushed with N2 (3x).
• N-(5-(2,2,2-Trifluoroethoxy)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide To an oven dried vial with a stir bar, N-(5- bromopyridin-3 -yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide -01 (0.02 g, 0.046 mmol), RockPhos (0.428 mg, 0.913 (0.418 mg, 0.456 ⁇ ), 2,2,2-trifluoroethanol (4.57 mg, 0.046 mmol) and K3P04 (0.015 g, 0.068 mmol)were added.
• N-(5-(Cyclopropylmethoxy)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide To an oven dried vial with a stir bar, N-(5- bromopyridin-3 -yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.04 g, 0.091 mmol), RockPhos (0.856 mg, 1.826 ⁇ 1), ⁇ (12(( ⁇ > ⁇ )3 (0.836 mg, 0.913 ⁇ ), cyclopropylmethanol (6.58 mg, 0.091 mmol) and K3P04 (0.029 g, 0.137 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (lmL) was added. The vial was degassed and flushed with N
• N-(5-Phenylpyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide To a microwave vial was added N-(5-bromopyridin-3- yl)-2-((6-(trifiuoromethyl)pyridin-2-yl)amino)isonicotinamide (0.02 g, 0.046 mmol), phenylboronic acid (5.57 mg, 0.046 mmol) and PdC12(dppf)-CH2C12Adduct (3.73 mg, 4.56 ⁇ ). The reaction mixture was degassed and flushed with N2 (3x).
• 5-(2-Fluorophenyl)pyridin-3-amine A mixture of Phosphoric acid, potassium salt (1.043 g, 4.91 mmol), PCy3 (0.019 g, 0.069 mmol), Pd2(dba)3 (0.026 g, 0.029 mmol), 5-bromopyridin-3-amine (0.5 g, 2.89 mmol) and (2-fiuorophenyl)boronic acid (0.607 g, 4.33 mmol) in DMF (5 mL)and water (0.5 mL) was heated at 100 °C under N2 overnight. The reaction was filtered through a silica plug and washed with ethyl acetate.
• the reaction was stirred at rt overnight.
• the reaction was diluted with ethyl acetate and satd sodium bicarbonate and water and dried over sodium sulfate.
• the solvent was evaporated and the residue was purified with prep LCMS to give desired prod.
• the solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (lmL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 110 °C for 3 hrs. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was dissolved in methanol/DMF, filtered and purified by prep LCMS to give desired prod.
• the reaction mixture was heated to 85 °C for 3h. LCMS showed desired prod.
• the reaction was diluted with ethyl acetate and satd ammonium chloride.
• the org layer was washed with water, brine and dried over sodium sulfate.
• the crude product was dissolved in a small amount of dichloromethane and charged to a 120 g silica gel cartridge which was eluted with 0-100% ethyl acetate / hexanes over a period of 60 mins.
• the desired fractions were combined and dried under vacuo to give 4-(5- aminopyridin-3-yl)benzonitrile (0.28 g, 1.434 mmol, 83 % yield).
• N-(5-(4-Cyanophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2- yl)amino)isonicotinamide N-(5-(4-Cyanophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2- yl)amino)isonicotinamide.
• 2-((6-cyanopyridin-2-yl)amino)isonicotinic acid (0.05 g, 0.208 mmol) and 4-(5-aminopyridin-3-yl)benzonitrile (0.041 g, 0.208 mmol) in Ethyl acetate (2 mL) was added DIEA (0.182 mL, 1.041 mmol) followed by 1- Propanephosphonic acid cyclic anhydride, 50% in EtOAc (0.243 mL, 0.416 mmol) dropwise.
• N-(5-Bromopyridin-3-yl)-2-((5-(l-cyanocyclopropyl)pyridin-2- yl)amino)isonicotinamide To an oven dried vial with a stir bar, brettphos precatalyst (2.73 mg, 3.41 ⁇ ), brett phos (1.797 mg, 3.41 ⁇ ), l-(6- chloropyridin-3-yl)cyclopropanecarbonitrile (0.061 g, 0.341 mmol), 2-amino-N-(5- bromopyridin-3-yl)isonicotinamide (0.1 g, 0.341 mmol) and K2C03 (0.071 g, 0.512 mmol) were added.
• the solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (lmL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 110 °C for 3 hrs. LCMS- showed a bit of prod with both s/m still present. The reaction was heated for 10 more hrs at 110 °C. LCMS showed no improvement. The reaction mixture was cooled, diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with brine and dried over sodium sulfate.
• N-(5-(4-Cyano-3-fluorophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2- yl)amino)isonicotinamide was added to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial was added N-(5-bromopyridin-3- yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide (0.03g, 0.076 mmol),(4-cyano-3- fiuorophenyl)boronic acid (0.013 g, 0.076 mmol) and PdC12(dppf)-CH2C12Adduct (0.012 g, 0.015 mmol).
• reaction mixture was degassed and flushed with N2 (3x). Then DMF (1 mL) was added and the system was degassed and flushed with N2(3x). SODIUM CARBONATE (0.076 mL, 0.152 mmol) was added and the system was degassed and flushed with N2(3x). The reaction mixture was heated to 85°C for 3 hrs. LCMS showed desired prod. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate.
• N-(5-(2-Cyano-3-fluorophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2- yl)amino)isonicotinamide was added to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial to a microwave vial was added N-(5-bromopyridin-3- yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide (0.03g, 0.076 mmol),(2-cyano-3- fiuorophenyl)boronic acid (0.013 g, 0.076 mmol) and PdC12(dppf)-CH2C12Adduct (0.012 g, 0.015 mmol).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biomedical Technology (AREA)
• Epidemiology (AREA)
• Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Immunology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pyridine Compounds (AREA)

Priority Applications (11)

Applications Claiming Priority (2)

Publications (1)

Family

ID=51982762

Family Applications (1)

Country Status (12)

Cited By (10)

Families Citing this family (3)

Citations (3)

Family Cites Families (7)

• 2014
  • 2014-11-03 SG SG11201603209XA patent/SG11201603209XA/en unknown
  • 2014-11-03 KR KR1020167014599A patent/KR102339227B1/ko active IP Right Grant
  • 2014-11-03 WO PCT/US2014/063691 patent/WO2015069594A1/en active Application Filing
  • 2014-11-03 EP EP14802990.3A patent/EP3066093B9/en active Active
  • 2014-11-03 US US15/033,813 patent/US9718804B2/en active Active
  • 2014-11-03 CN CN201480072336.7A patent/CN105849098A/zh active Pending
  • 2014-11-03 MX MX2016005760A patent/MX2016005760A/es unknown
  • 2014-11-03 EA EA201690844A patent/EA201690844A1/ru unknown
  • 2014-11-03 AU AU2014347027A patent/AU2014347027A1/en not_active Abandoned
  • 2014-11-03 JP JP2016528235A patent/JP2016535755A/ja active Pending
  • 2014-11-03 CA CA2929528A patent/CA2929528A1/en not_active Abandoned
• 2016
  • 2016-05-03 IL IL245442A patent/IL245442A0/en unknown

Patent Citations (3)

Non-Patent Citations (7)

Also Published As

Similar Documents

Legal Events